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Hormannsperger, G.* ; Clavel, T.* ; Hoffmann, M.* ; Reiff, C.* ; Kelly, D.* ; Loh, G.* ; Blaut, M.* ; Hölzlwimmer, G. ; Laschinger, M.* ; Haller, D.*

Post-translational inhibition of IP-10 secretion in IEC by probiotic bacteria: impact on chronic inflammation.

PLoS ONE 4:e4365 (2009)
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BACKGROUND: Clinical and experimental studies suggest that the probiotic mixture VSL#3 has protective activities in the context of inflammatory bowel disease (IBD). The aim of the study was to reveal bacterial strain-specific molecular mechanisms underlying the anti-inflammatory potential of VSL#3 in intestinal epithelial cells (IEC). METHODOLOGY/PRINCIPAL FINDINGS: VSL#3 inhibited TNF-induced secretion of the T-cell chemokine interferon-inducible protein (IP-10) in Mode-K cells. Lactobacillus casei (L. casei) cell surface proteins were identified as active anti-inflammatory components of VSL#3. Interestingly, L. casei failed to block TNF-induced IP-10 promoter activity or IP-10 gene transcription at the mRNA expression level but completely inhibited IP-10 protein secretion as well as IP-10-mediated T-cell transmigration. Kinetic studies, pulse-chase experiments and the use of a pharmacological inhibitor for the export machinery (brefeldin A) showed that L. casei did not impair initial IP-10 production but decreased intracellular IP-10 protein stability as a result of blocked IP-10 secretion. Although L. casei induced IP-10 ubiquitination, the inhibition of proteasomal or lysosomal degradation did not prevent the loss of intracellular IP-10. Most important for the mechanistic understanding, the inhibition of vesicular trafficking by 3-methyladenine (3-MA) inhibited IP-10 but not IL-6 expression, mimicking the inhibitory effects of L. casei. These findings suggest that L. casei impairs vesicular pathways important for the secretion of IP-10, followed by subsequent degradation of the proinflammatory chemokine. Feeding studies in TNF(DeltaARE) and IL-10(-/-) mice revealed a compartimentalized protection of VSL#3 on the development of cecal but not on ileal or colonic inflammation. Consistent with reduced tissue pathology in IL-10(-/-) mice, IP-10 protein expression was reduced in primary epithelial cells. CONCLUSIONS/SIGNIFICANCE: We demonstrate segment specific effects of probiotic intervention that correlate with reduced IP-10 protein expression in the native epithelium. Furthermore, we revealed post-translational degradation of IP-10 protein in IEC to be the molecular mechanism underlying the anti-inflammatory effect.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Animals; Autophagy/drug effects; Bacterial Proteins/metabolism; Chemokine CXCL10/secretion*; Chemotaxis/drug effects; Chronic Disease; Colitis/microbiology; Colitis/pathology; Epithelial Cells/cytology; Epithelial Cells/drug effects; Epithelial Cells/microbiology*; Epithelial Cells/secretion*; Humans; Inflammation/microbiology*; Intestines/cytology*; Intracellular Space/drug effects; Intracellular Space/metabolism; Lactobacillus casei/drug effects; Lactobacillus casei/metabolism*; Lysosomes/drug effects; Ly
Language english
Publication Year 2009
HGF-reported in Year 0
ISSN (print) / ISBN 1932-6203
Journal PLoS ONE
Quellenangaben Volume: 4, Issue: 2, Pages: , Article Number: e4365 Supplement: ,
Publisher Public Library of Science (PLoS)
Publishing Place Lawrence, Kan.
Reviewing status Peer reviewed
Institute(s) Institute of Pathology (PATH)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-500300-001
PubMed ID 19197385
DOI 10.1371/journal.pone.0004365
WOS ID 000265483700003
Scopus ID 84856825811
Erfassungsdatum 2009-12-31
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